Change Impact Analysis for Evolving Configuration Decisions in Product Line Use Case Models

Product Line Engineering is becoming a key practice in many software development environments where complex systems are developed for multiple customers with varying needs. In many business contexts, use cases are the main artifacts for communicating requirements among stakeholders. In such contexts, Product Line (PL) use cases capture variable and common requirements while use case-driven configuration generates Product Specific (PS) use cases for each new customer in a product family. In this paper, we propose, apply, and assess a change impact analysis approach for evolving configuration decisions in PL use case models. Our approach includes: (1) automated support to identify the impact of decision changes on prior and subsequent decisions in PL use case diagrams and (2) automated incremental regeneration of PS use case models from PL use case models and evolving configuration decisions. Our tool support is integrated with IBM Doors. Our approach has been evaluated in an industrial case study, which provides evidence that it is practical and beneficial to analyze the impact of decision changes and to incrementally regenerate PS use case models in industrial settings

PUMConf: A Tool to Configure Product Specific Use Case and Domain Models in a Product Line

We present PUMConf, a tool for supporting configuration that currently focuses on requirements and enables effective product line management in the context of use case-driven development. By design, it relies exclusively on variability modeling for artifacts that are commonly used in such contexts (i.e., use case diagram, specifications and domain model). For given Product Line (PL) use case and domain models, PUMConf checks the consistency of the models, interactively receives configuration decisions from analysts, automatically checks decision consistency, and generates Product Specific (PS) use case and domain models from the PL models and decisions. It has been evaluated on an industrial case study in the automotive domain

Combination of nitrate (N, O) and boron isotopic ratios with microbiological indicators for the determination of nitrate sources in karstic groundwater

International audienceA new approach based on measurements of nitrate and boron isotopic composition associated with microbiological indicators for the determination of nitrate origin in karstic groundwater (SW, France) is presented. Nitrate and boron isotopic data indicate an animal source of nitrate (delta N-15-NO3- > 5 parts per thousand, delta O-18-NO3- < 10 parts per thousand and delta B-11 similar to 25 parts per thousand). Microorganism detection (bacteriophages) confirmed contamination from animal sources and proved fast water transfer (2-3 days) from surface to groundwater

Software Quality Objectives for Source Code

International audienceThe MathWorks - Renault SA - PSA Peugeot Citroën - Delphi Diesel System - Valeo group wrote together a code quality standard from scratch. This document describes how the code standard places the proof of absence of run-time errors at the centre of its software quality model. It details how the following elements of the quality model co-exist together with the supplier code life cycle: MISRA-C coding standard, the absence of run-time errors and some code complexity metrics. Additionally, this document describes how the Automotive manufacturers and the suppliers have to agree on and achieve different Software Quality Objectives according to the code life cycle stage and the safety aspects of the application.Finally, the document illustrates that standard with the PolySpace product and details how the product can help both the automotive manufacturer and the supplier working with this standard

Dogs used as a large animal model of obesity-related insulin resistance

As for ethical and other reasons, studies of the pathophysiological mechanisms of obesity and its association with insulin resistance (IR) cannot be performed in man, researchers have to use appropriate animal models. Although dogs fed on a high-fat diet seem to meet the requirements to study this human syndrome, the canine model has hardly been used. Our objective was to study the lipoprotein metabolism and reverse cholesterol transport in healthy dogs, then in dogs with insulin resistance. We also aimed to describe the plasmatic changes associated with insulin resistance, and quantify the expression of genes involved in this disorder, in insulin target tissues (visceral adipose tissue and skeletal muscle). In healthy dogs, apoB100 exclusively appears in VLDL, whose high production is associated with a high fractional catabolism (5-fold greater than that of human). LDL-apoB100 metabolism is similar in dogs and humans. Our results showed that the healthy dog does not exhibit any CETP activity in vivo, and that reverse cholesterol transport is very active, with substantial selective uptake of HDL esterified cholesterol. Consequently, among species with no CETP activity, dogs provide an adequate model to study changes in this selective cholesterol uptake. The anomalies observed in lipoprotein profiles produced by FPLC in IR obese dogs were identical to those seen in IR man. Insulin resistance is associated with a decreased production of LDL apo B100, due to a reduced production, despite the increased catabolism. Both transcription and plasmatic results confirmed those found in man (overexpression of leptin mRNA, underexpression of adiponectin, GLUT4, LPL, PPAR and UCP mRNAs). Therefore, dogs could provide a useful research model, particularly to elucidate the molecular mechanisms involved in the development of insulin resistance and dyslipidemia.Pour des raisons notamment éthiques, il n'est pas possible d'étudier chez l'homme les phénomènes physiopathologiques associés à l'évolution conjointe de l'obésité et de la baisse de sensibilité à l'insuline. L'établissement de modèles animaux reflétant la pathologie humaine paraît donc indispensable. Le chien soumis à un régime hyperlipidique semblait répondre aux critères de sélection d'un modèle adapté à l'étude de ce syndrome. Il n'avait cependant été que peu exploré. Le but de notre travail a été d'une part, d'étudier le métabolisme des lipoprotéines et le transport inverse du cholestérol chez le chien sain, puis chez le chien insulinorésistant (IR) et d'autre part, de caractériser l'évolution des modifications plasmatiques associées à l'insulinorésistance, puis de quantifier, au sein de certains tissus cibles de l'insuline (tissus adipeux viscéral et musculaire), l'expression de gènes impliqués dans ce désordre métabolique. Chez le chien sain, l'apo B100 (apolipoprotéine B100) apparaît exclusivement dans les VLDL dont la production élevée est associée à un catabolisme important, égal à 5 fois celui de l'homme. Ces lipoprotéines subissent une lipolyse partielle, formant les LDL qui contiennent donc aussi de l'apoB100. L'apoB100 des LDL a un métabolisme similaire à celui de l'homme. Le chien sain ne manifeste pas d'activité CETP (cholesterol ester tranfer protein) in vivo, mais présente un transport inverse du cholestérol très actif, notamment associé à une importante capture sélective du cholestérol estérifié des HDL. Le chien pourrait donc s'avérer le meilleur modèle pour l'étude de la modulation de cette voie de retour du cholestérol. Les profils lipidiques des lipoprotéines, obtenus par chromatographie FPLC chez le chien obèse IR, ont montré les mêmes perturbations que chez l'homme IR. La production d'apo B100 dans les VLDL est augmentée et la lipolyse diminuée. La concentration en apo B100 des LDL est diminuée, conséquence d'une production réduite et d'un catabolisme augmenté. Les résultats obtenus aux niveaux transcriptionnel et plasmatique sont également conformes aux observations effectuées chez l'homme (surexpression du gène de la leptine, sous-expression de celui de l'adiponectine, du GLUT4, de la lipoprotéine lipase, des PPAR et des UCP notamment). Sur les deux plans de l'étude, nos résultats confirment que le chien pourrait constituer un bon modèle d'étude, notamment pour l'élucidation des mécanismes moléculaires impliqués dans le développement de l'insulinorésistance et des dyslipidémies

Metabolism

Background: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. Methods: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks. Results: Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. Conclusion: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HfpEF

The Hepatic Compensatory Response to Elevated Systemic Sulfide Promotes Diabetes

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst−/− mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst−/− mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst−/− mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells

Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention

Taxonomy of the order Mononegavirales : update 2016

In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV)